A clinical trial for psoriasis with novel single-cell genomic techniques to understand regulatory immunity behind long-term disease remission off drug induced by short-term IL-23 inhibition
使用新型单细胞基因组技术进行银屑病临床试验,以了解短期 IL-23 抑制诱导的药物长期疾病缓解背后的调节免疫
基本信息
- 批准号:10340103
- 负责人:
- 金额:$ 16.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-18 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AnatomyAntibodiesAntigen-Presenting CellsBiologicalBiological MarkersBiological ProductsBiopsyBiopsy SpecimenCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCell CommunicationCellsChromatinClinicalClinical TrialsDataDendritic CellsDigestionDiseaseDisease ProgressionDisease remissionDoseEnzymesEpidermisFOXP3 geneGene ExpressionGenomicsGoalsHourHumanImmuneImmune System DiseasesImmune ToleranceImmune responseImmunityImmunobiologyInjectionsKLRB1 geneLesionMachine LearningMentorsMessenger RNAMicrofluidicsMolecularNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNatural Killer CellsOutcomePathogenicityPathologicPatientsPharmaceutical PreparationsPhasePhenotypePsoriasisPublic HealthRecurrenceRegulationRegulatory T-LymphocyteResearchSkinT-LymphocyteTechniquesTestingbasecell typechronic inflammatory diseaseclinical applicationcombinatorialcytokinedrug clearancegenetic signaturegenomic datahealthy volunteerindexinginnovationinterleukin-23keratinocytemelanocytenovelpredictive modelingpreventprogramsrestorationsingle-cell RNA sequencingskin disordertranscriptometranscriptome sequencing
项目摘要
Although highly effective, biologics targeting IL-23/Th17 axis should be continuously injected to
suppress recurrence of psoriasis. My long-term goal is to cure psoriasis without recurrence guided by
personal immune tolerance. The overall objectives in this application are to (i) identify regulatory immune
cell interactions induced by anti-IL-23p19 antibody administration in the skin of patients whose psoriasis
is cleared without recurrence and (ii) develop pre-treatment predictive models for psoriasis patients that
anticipate disease recurrence after short-term anti-IL-23p19 antibody injection. The central hypothesis is
that IL-23p19 inhibition promotes regulatory immune cells in psoriasis patients whose disease is cleared
without recurrence, and their pre-treatment single-cell immune signatures are different from those of patients
whose disease recurs. The rationale for this project is that molecular evidence of immune tolerance
induction by IL-23p19 inhibition in human skin is likely to offer a strong clinical framework whereby new
strategies to prevent recurrence of chronic inflammatory diseases can be developed. The central hypothesis
will be tested by pursuing two specific aims: 1) Testing the hypothesis that regulatory immune cell
interactions are promoted by short-term anti-IL-23p19 antibody administration in the skin of psoriasis patients
whose disease becomes clear without recurrence; and 2) Developing predictive models with pretreatment
skin biopsy single-cell genomic data that anticipate long-term disease clearance off drug after
short-term anti-IL-23p19 antibody administration. To achieve the specific aims, we have recently developed
two innovative complementary single-cell approaches to obtain gene expression profiles of heterogeneous
immune cells from psoriasis and control skin without enzyme digestion. The first single-cell experimental
approach is microfluidic partitioning of emigrating cells from human skin after 48-hour incubation
in culture medium without enzyme digestion, which empowers single-cell transcriptomic profiling of
heterogeneous immune cells and keratinocytes in different layers of epidermis under ex vivo condition.
The second single-cell experimental approach is Combinatorial indexing RNA sequencing, developed by
the co-mentor of the proposal, which enables co-profiling transcriptome and single-cell chromatin accessibility.
At the completion of the proposed research, our expected outcomes are to have novel single-cell
genomic techniques to study immune cell interactions in human skin, defined single-cell gene signatures
of regulatory immune cells that are promoted by anti-IL-23p19 antibody administration in psoriasis skin,
and the ability to elucidate how pathologic immunity is suppressed at the single-cell level by highly effective
biologics. We also expect to have pre-treatment biomarkers that can predict long-term disease clearance
off drugs after short-term anti-IL-23p19 antibody administration.
虽然非常有效,但针对 IL-23/Th17 轴的生物制剂应持续注射
抑制牛皮癣的复发。我的长期目标是治愈牛皮癣而不复发
个人免疫耐受。本申请的总体目标是 (i) 识别监管免疫
银屑病患者皮肤中施用抗 IL-23p19 抗体诱导的细胞相互作用
被清除而不会复发,并且(ii)为银屑病患者开发治疗前预测模型,
预测短期抗 IL-23p19 抗体注射后疾病复发。中心假设是
IL-23p19 抑制可促进疾病被清除的银屑病患者的调节性免疫细胞
无复发,治疗前单细胞免疫特征与患者不同
谁的疾病复发。该项目的基本原理是免疫耐受的分子证据
通过抑制人类皮肤中的 IL-23p19 进行诱导可能会提供一个强大的临床框架,从而使新的
可以制定预防慢性炎症疾病复发的策略。中心假设
将通过追求两个具体目标来进行测试:1)测试调节性免疫细胞的假设
在银屑病患者皮肤中短期施用抗 IL-23p19 抗体可促进相互作用
疾病已明确且未复发; 2) 通过预处理开发预测模型
皮肤活检单细胞基因组数据可预测药物治疗后长期疾病清除
短期抗IL-23p19抗体施用。为了实现特定目标,我们最近开发了
两种创新的互补单细胞方法来获得异源基因表达谱
来自牛皮癣的免疫细胞无需酶消化即可控制皮肤。第一个单细胞实验
方法是在 48 小时孵育后对来自人体皮肤的迁移细胞进行微流体分离
在没有酶消化的培养基中,这使得单细胞转录组分析成为可能
离体条件下表皮不同层的异质免疫细胞和角质形成细胞。
第二种单细胞实验方法是组合索引 RNA 测序,由
该提案的共同导师,该提案能够对转录组和单细胞染色质可及性进行共同分析。
在完成拟议的研究后,我们的预期结果是获得新型单细胞
研究人类皮肤免疫细胞相互作用的基因组技术,定义单细胞基因特征
在银屑病皮肤中施用抗 IL-23p19 抗体可促进调节性免疫细胞的生长,
以及阐明如何通过高效的方法在单细胞水平上抑制病理免疫的能力
生物制剂。我们还期望有可以预测长期疾病清除的治疗前生物标志物
短期抗 IL-23p19 抗体给药后停药。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Jaehwan Kim其他文献
Jaehwan Kim的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Jaehwan Kim', 18)}}的其他基金
A clinical trial for psoriasis with novel single-cell genomic techniques to understand regulatory immunity behind long-term disease remission off drug induced by short-term IL-23 inhibition
使用新型单细胞基因组技术进行银屑病临床试验,以了解短期 IL-23 抑制诱导的药物长期疾病缓解背后的调节免疫
- 批准号:
10685945 - 财政年份:2022
- 资助金额:
$ 16.89万 - 项目类别:
相似海外基金
University of Aberdeen and Vertebrate Antibodies Limited KTP 23_24 R1
阿伯丁大学和脊椎动物抗体有限公司 KTP 23_24 R1
- 批准号:
10073243 - 财政年份:2024
- 资助金额:
$ 16.89万 - 项目类别:
Knowledge Transfer Partnership
Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease
天然抗体和 B1 细胞在纤维增生性肺病中的作用
- 批准号:
10752129 - 财政年份:2024
- 资助金额:
$ 16.89万 - 项目类别:
CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies
职业:利用化学多样化的抗体发现下一代蛋白酶抑制剂
- 批准号:
2339201 - 财政年份:2024
- 资助金额:
$ 16.89万 - 项目类别:
Continuing Grant
Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
- 批准号:
MR/Y008693/1 - 财政年份:2024
- 资助金额:
$ 16.89万 - 项目类别:
Research Grant
Discovery of novel nodal antibodies in the central nervous system demyelinating diseases and elucidation of the mechanisms through an optic nerve demyelination model
发现中枢神经系统脱髓鞘疾病中的新型节点抗体并通过视神经脱髓鞘模型阐明其机制
- 批准号:
23K14783 - 财政年份:2023
- 资助金额:
$ 16.89万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of the mechanisms controlling the physicochemical properties and functions of supercharged antibodies and development of their applications
阐明控制超电荷抗体的理化性质和功能的机制及其应用开发
- 批准号:
23KJ0394 - 财政年份:2023
- 资助金额:
$ 16.89万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Developing first-in-class aggregation-specific antibodies for a severe genetic neurological disease
开发针对严重遗传神经系统疾病的一流聚集特异性抗体
- 批准号:
10076445 - 财政年份:2023
- 资助金额:
$ 16.89万 - 项目类别:
Grant for R&D
PLA2G2D Antibodies for Cancer Immunotherapy
用于癌症免疫治疗的 PLA2G2D 抗体
- 批准号:
10699504 - 财政年份:2023
- 资助金额:
$ 16.89万 - 项目类别:
Genetic adjuvants to elicit neutralizing antibodies against HIV
基因佐剂可引发抗艾滋病毒中和抗体
- 批准号:
10491642 - 财政年份:2023
- 资助金额:
$ 16.89万 - 项目类别:
Novel Immunogens to Elicit Broadly Cross-reactive Antibodies That Target the Hemagglutinin Head Trimer Interface
新型免疫原可引发针对血凝素头三聚体界面的广泛交叉反应抗体
- 批准号:
10782567 - 财政年份:2023
- 资助金额:
$ 16.89万 - 项目类别:














{{item.name}}会员




